Journal article
Activation of heme biosynthesis by a small molecule that is toxic to fermenting Staphylococcus aureus
Proceedings of the National Academy of Sciences - PNAS, Vol.110(20), pp.8206-8211
05/14/2013
DOI: 10.1073/pnas.1303674110
PMCID: PMC3657828
PMID: 23630262
Abstract
Staphylococcus aureus is a significant infectious threat to global public health. Acquisition or synthesis of heme is required for S. aureus to capture energy through respiration, but an excess of this critical cofactor is toxic to bacteria. S. aureus employs the heme sensor system (HssRS) to overcome heme toxicity; however, the mechanism of heme sensing is not defined. Here, we describe the identification of a small molecule activator of HssRS that induces endogenous heme biosynthesis by perturbing central metabolism. This molecule is toxic to fermenting S. aureus, including clinically relevant small colony variants. The utility of targeting fermenting bacteria is exemplified by the fact that this compound prevents the emergence of antibiotic resistance, enhances phagocyte killing, and reduces S. aureus pathogenesis. Not only is this small molecule a powerful tool for studying bacterial heme biosynthesis and central metabolism; it also establishes targeting of fermentation as a viable antibacterial strategy.
Details
- Title: Subtitle
- Activation of heme biosynthesis by a small molecule that is toxic to fermenting Staphylococcus aureus
- Creators
- Laura A. Mike - Vanderbilt UniversityBrendan F. Dutter - Vanderbilt University Medical CenterDevin L. Stauff - Vanderbilt UniversityJessica L. Moore - Vanderbilt UniversityNicholas P. Vitko - University of North Carolina at Chapel HillOlusegun Aranmolate - Vanderbilt UniversityThomas E. Kehl-Fie - Vanderbilt UniversitySarah Sullivan - University of Notre DamePaul R. Reid - Vanderbilt University Medical CenterJennifer L. DuBois - SRI InternationalAnthony R. Richardson - University of North Carolina at Chapel HillRichard M. Caprioli - Vanderbilt UniversityGary A. Sulikowski - Vanderbilt University Medical CenterEric P. Skaar - Vanderbilt University Medical Center
- Resource Type
- Journal article
- Publication Details
- Proceedings of the National Academy of Sciences - PNAS, Vol.110(20), pp.8206-8211
- Publisher
- Natl Acad Sciences
- DOI
- 10.1073/pnas.1303674110
- PMID
- 23630262
- PMCID
- PMC3657828
- ISSN
- 0027-8424
- eISSN
- 1091-6490
- Number of pages
- 6
- Grant note
- T32 GM008320 / Vanderbilt Chemical Biology Interface Training Program Grant T32HL069765 / NATIONAL HEART, LUNG, AND BLOOD INSTITUTE; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Heart Lung & Blood Institute (NHLBI) R01AI069233 / NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Allergy & Infectious Diseases (NIAID) 8p41GM103391-3 / NIH/National Institute of General Medical Sciences Grant T32GM065086 / NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of General Medical Sciences (NIGMS) U54 AI057157-06 / Searle Scholars Program, National Institutes of Health (NIH) Grant from the Southeastern Regional Center of Excellence for Emerging Infections and Biodefense AI069233; AI073843; T32 HL069765; T32 GM065086; F32 AI100480; R01GM090260 / NIH; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA P41RR031461 / NATIONAL CENTER FOR RESEARCH RESOURCES; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Center for Research Resources (NCRR) American Heart Association Postdoctoral Fellowship; American Heart Association
- Language
- English
- Date published
- 05/14/2013
- Academic Unit
- Microbiology and Immunology
- Record Identifier
- 9984618649202771
Metrics
12 Record Views